Tacrolimus: 10 years of successful clinical application

Abstract


Tacrolimus (FK506) is the first drug from the new class of drugs - calcineurin inhibitors. It has a great potential and can change
the current approaches to treatment of different dermatoses. Topical forms of Tacrolimus are activated due to the effect on T-lymphocyte
signal transduction, and they also inhibit gene transcription. As a result, the T-cell response to antigens is alleviated.
Percutaneous absorption of Tacrolimus in affection foci is higher than in healthy skin. Due to this a smaller amount of the drug
is absorbed by the skin as long as the skin is healed. Systemic absorption of Tacrolimus is low in the course of treatment. The
maximum clinical experience has been gained in the field of applying Tacrolimus for treatment of atopic dermatitis. In a number of
clinical studies, 0.03-0.3% Tacrolimus ointment efficiently reduced the severity of symptoms and course of atopic dermatitis in
adults and children. Moreover, topical treatment with Tacrolimus did not involve any substantial toxic effects. The patients most often
complained of local irritations in the area where the ointment was applied, which were transient by nature and did not demand
the drug withdrawal. Today Tacrolimus is a valuable and safer alternative to glucocorticosteroids for treatment of atopic dermatitis.
It can also be used for treating other dermatoses, which demands additional all-round examination.

About the authors

A L Bakulev

A L Bakulev

References

  1. Ruzicka T, Assmann T, Homey B. Tacrolimus: The drug for the turn of the millennium? Arch Dermatol 1999; 16: 574-580.
  2. Lawrence ID. Tacrolimus (FK506): experience in dermatology. Dermatol Ther 1998; 5: 74-84.
  3. Michel G, Kemeny L, Homey B, Ruzicka T. FK506 in the treatment of inflammatory skin disease: promises and perspectives. Immunol Today 1996; 17: 106-108.
  4. Fleischer AB. Treatment of atopic dermatitis: Role of tacrolimus ointment as a topical noncorticosteroid therapy. J Allergy Clin Immunol 2000; 104: S126-S130.
  5. Wollenberg A, Bieber T. FK-506/Tacrolimus. In: Burg G, Dummer RG, editors. Strategies for Immunointerventions in Dermatology. Springer-Verlag, Heidelberg, 1997: 53-57.
  6. Columbo M, Bochner BS, Marone G. Human skin mast cells express functional beta1 integrins that mediate adhesion to extracellular martix proteins. J Immunol 1995; 154: 6058-6064.
  7. Panhans-Gro? A, Novak N, Kraft S et al. Human epidermal Langerhans' cells are targets for the immnosuppressive macrolide tacrolimus (FK506). J Allergy Clin Immunol 2001; 107: 345-352.
  8. Reitamo S. Tacrolimus: a new topical immunomodulatory therapy for atopic dermatitis. J Allergy Clin Immunol 2001; 107: 445-448.
  9. Nagai H, Hiyama H, Matsuo A et al. FK-506 and cyclosporin A potentiate the IgE antibody production by contact sensitization with hapten in mice. J Pharmacol Exp Ther 1997; 283: 321-327.
  10. Homey B, Assmann T, Vohr H-W et al. Topical FK506 suppresses cytokine and costimulatory molecule expression in epidermal and local draining lymph node cells during primary skin immune responses. J Immunol 1998; 160: 5331-5340.
  11. Leung DYM, Soter NA. Cellular and immunologic mechanisms in atopic dermatitis. J Am Acad Dermatol 2001; 44: S1-S12.
  12. Williams HC. Epidemiology of atopic dermatitis. Clin Exp Dermatol 2000; 25: 522-529.
  13. Knoell KA, Greer KE. Atopic dermatitis. Pediatr Rev 1999; 20: 46-51.
  14. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1980; 92: 44-47.
  15. Noble WC. Skin bacteriology and the role of Staphylococcus aureus in infection. Br J Dermatol 1998; 139: 9-12.
  16. Abeck D, Mempel M. Staphylococcus aureus colonization in atopic dermatitis and its therapeutic implications. Br J Dermatol 1998; 139: 13-16.
  17. Leung DYM, Hauk P, Strickland I et al. The role of superantigens in human diseases: therapeutic implications for the treatment of skin diseases. Br J Dermatol 1998; 139: 17-29.
  18. Nakagawa H, Etoh T, Yokota Y et al. Tacrolimus has antifungal activities against Malassezia furfur isolated from healthy adults and patients with atopic dermatitis. Clin Drug Invest 1996; 12: 244-250.
  19. Leung DYM. Pathogenesis of atopic dermatitis. J Allergy Clin Immunol 1999; 104: S99-S108.
  20. Muschen A, Mirmohammadsadegh A, Jarzebska-Deussen B et al. Differential IL-10 receptor gene expression in acute versus chronic atopic eczema. Modulation by immunosuppressive drugs and cytokines in normal cultured keratinocytes. Inflamm Res 1999; 48: 539-543.
  21. de Paulis A, Stellato C, Cirillo R et al. Anti-inflammatory effect of FK-506 on human skin mast cells. J Invest Dermatol 1992; 99: 723-728.
  22. Funk JO, Maibach HI. Horizons in pharmacologic intervention in allergic contact dermatitis. J Am Acad Dermatol 1994; 31: 999-1014.
  23. Gordon K, Guitart J, Victor T et al. Topical triamcinolone and tacrolimus differ in their in vivo effects on Langerhans cells during the treatment of atopic dermatitis. J Invest Dermatol 1999; 11: Abstract 654.
  24. Wollenberg A, Sharma S, von Bubnoff D et al. Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen-presenting dendritic cells in atopic dermatitis. J Allergy Clin Immunol 2001; 107: 519-525.
  25. Lemster B, Rilo HR, Carroll PB et al. FK506 inhibits cytokine gene and adhesion molecule expression in psoriatic skin lesions. Ann NY Acad Sci 1993; 696: 250-256.
  26. Thomson AW, Nalesnik M, Abu-Elmagd K, Starzl TE. Influence of FK506 on T lymphocytes, Langerhans' cells and the expression of cytokine receptors and adhesion molecules in psoriatic skin lesions: a preliminary study. Transplant Proc 1991; 23: 3330-3331.
  27. Jun Y, Sheng-Li C, Xiao-Lin W et al., Meta-analysis of tacrolimus ointment for atopic dermatitis in pediatric patients. Ped. Derm. Vol. 25 No.1 Jan/Feb 2008
  28. Schultz BS, Michel G, Wagner S et al. Increased expression of epidermal IL-8 receptor in psoriasis; down-regulation by FK-506 in vitro. J Immunol 1993; 151: 4399-4406.
  29. Sawada S, Suzuki G, Kawase Y, Takaku F. Novel immunosuppressive agent, FK506. In vitro effects on the cloned T cell activation. J Immunol 1987; 139: 1797-1803.
  30. Lemster B, Carroll PB, Rilo HR et al. IL-8/IL-8 receptor expression in psoriasis and the response to systemic tacrolimus (FK506) therapy. Clin Exp Immunol 1995; 99: 148-154.
  31. Michel G, Auer H, Kemeny L et al. Antioncogene p53 and mitogenic cytokine interleukin-8 aberrantly expressed in psoriatic skin are inversely regulated by the antipsoriatic drug tacrolimus (FK506). Biochem Pharmacol 1996; 51: 1315-1320.
  32. Bieber T. Topical tacrolimus (FK506): a new milestone in the management of atopic dermatitis. J Allergy Clin Immunol 1998; 102: 555-557.
  33. Ruzicka T, Bieber T, Schopf E et al. A short-term trial of tacrolimus ointment for atopic dermatitis. N Engl J Med 1997; 337: 816- 821.
  34. Alaiti S, Kang S, Fiedler VC et al. Tacrolimus (FK506) ointment for atopic dermatitis: a phase I study in adults and children. J Am Acad Dermatol 1998; 38: 69-76.
  35. Hanifin JM, Chan S. Biochemical and immunologic mechanisms in atopic dermatitis: New targets for emerging therapies. J Am Acad Dermatol 1999; 41: 72-77.
  36. Lauerma AI, Surber C, Maibach HI. Absorption of topical tacrolimus (FK506) in vitro through human skin: comparison with cyclosporine A. Skin Pharmacol 1997; 10: 230-234.
  37. Laurema AI, Granlund H, Reitamo S. Use of the newer immunosuppressive agents in dermatology. Bio Drugs 1997; 8: 96-106.
  38. Shirbacheh MV, Jones JW, Harralson TA et al. Pharmacokinetics of intra-arterial delivery of tacrolimus to vascularly isolated rabbit forelimb. J Pharmacol Exp Ther 1999; 289: 1196-1201.
  39. Perego C, Lattuada D, Casnici C et al. Evidence that SMS 201- 995 enhances the immunosuppressive effect of FK506. Int J Immunopharmacol 1998; 20: 479-490.
  40. Przepiorka D, Blamble D, Hilsenbeck S et al. Tacrolimus clearance is age-dependent within the pediatric population. Bone Marrow Transplant 2000; 26: 601-605.
  41. Magee CC, Denton MD, Milford EL. Immunosuppressive agents in organ transplantation. Hosp Med 1999; 60: 364-369.
  42. Iwata H, Nagano T, Toyo-oka K et al. Suppression of allograft responses by combining alloantigen-specific i.v. pre-sensitization with suboptimal doses of rapamycin. Int Immunol 1994; 6: 93-99.
  43. Johnston A, Holt DW. Therapeutic drug monitoring of immunosuppressant drugs. Br J Clin Pharmacol 1999; 47: 339-350.
  44. Min Z, Jones NF. Limb transplantation in rats: Immunosuppression with FK-506. J Hand Surg 1995; 20A: 77-87.
  45. Hirai T, Waddell TK, Puskas JD et al. Prolonged lung allograft survival with a short course of FK506. J Thorac Cardiovasc Surg 1993; 105: 1-8.
  46. Dubernard J-M, Owen E, Herzberg G et al. Human hand allograft: report on first 6months. Lancet 1999; 353: 1320.
  47. Muramatsu K, Doi K, Kawai S. Limb allotransplantation in rats: Combined immunosuppression by FK-506 and 15-Deoxyspergualin. J Hand Surg 1999; 24: 586-593.
  48. Cetinkale O, Cizmeci O, Ayan F et al. The use of FK506 and skin allografting for the treatment of severe burns in an animal model. Br J Plastic Surg 1993; 46: 410-415.
  49. Uchiyama H, Kong Y-Y, Kishihara K et al. Approach to withdrawal from tacrolimus in a fully allogeneic murine skin graft model. Immunology 1999; 97: 294-300.
  50. Ohashi Y, Minegishi M, Fujie H et al. Successful treatment of steroid- resistant severe acute GVHD with 24-h continuous infusion of FK506. Bone Marrow Transplant 1997; 19: 625-627.
  51. Nakamura H, Nakao T, Ujiie H et al. Induction of autologous graft-versus-host disease after autologous peripheral blood stem cell transplantation. J Allergy Clin Immunol 1999; 103: S457-S461.
  52. Ueno NT, Rondon G, Mirza NQ et al. Allogeneic peripheral-blood progenitor-cell transplantation for poor-risk patients with metastatic breast cancer. J Clin Oncol 1998; 16: 986-993.
  53. Worth LL, Tran H, Petropoulos D et al. Hematopoietic stem cell transplantation for childhood myeloid malignancies after highdose thiotepa, busulfan and cyclophosphamide. Bone Marrow Transplant 1999; 24: 947-952.
  54. Boehringer M, Schwartz A, Keller F. Kaposi's sarcoma after renal transplantation: treatment with liposomal doxorubicin. Nephrol Dial Transplant 1999; 14: 1342-1345.
  55. Woo L, Wright TM, Lemster B et al. Combined effects of FK506 (tacrolimus) and cyclophosphamide on atypical B22+ T cells, cytokine gene expression and disease activity in MRL/MpJ-lpr/lpr mice. Clin Exp Immunol 1995; 100: 118-125.
  56. Nagasaki Y, Matsubara Y, Takano H et al. Reversal of hypopigmintation in phenylketonuria mice by adenovirus-mediated gene transfer. Pediatr Res 1999; 45: 465-473.
  57. Koga T, Yano T, Ichikawa Y et al. Pulmonary infiltrates recovered by FK506 in a patient with Behcet's disease. Chest 1993; 104: 309-311.
  58. Jegasothy BV, Ackerman CD, Todo S et al. Tacrolimus (FK506) - A new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol 1992; 128: 781-785.
  59. Abu-Elmagd K, Jegasothy BV, Ackerman CD et al. Efficacy of FK506 in the treatment of recalcitrant pyoderma gangrenosum. Transplant Proc 1991; 23: 3328-3329.
  60. Hanifin JM, Ling MR, Langley R et al. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: Part I, efficacy. J Am Acad Dermatol 2001; 44: S28-S38.
  61. Kang S. Tacrolimus ointment (TO) for adults with moderate to severe atopic dermatitis (AD): a dose escalation study. J Invest Dermatol 1998; 110: Abstract 681.
  62. Gutgesell C, Jung T, Reich K et al. Double-blind hydrocortisonecontrolled tacrolimus ointment for atopic dermatitis. J Invest Dermatol 1998; 110: Abstract 681.
  63. Nakagawa H, Etoh T, Ishibashi Y et al. Effects of tacrolimus (FK506) ointment for facial atopic dermatitis 761-764. Madrid, Spain, 24 June 1995. XVI European Congress of Allergology and Clinical Immonology Conference Proceeding, 1995.
  64. Aoyama H, Tabata N, Tanaka M et al. Successful treatment of resistant facial lesions of atopic dermatitis with 0.1% FK506 ointment. Br J Dermatol 1995; 133: 494-496.
  65. Drake L, Prendergast M, Maher R et al. The impact of tacrolimus ointment on health-related quality of life of adult and pediatric patients with atopic dermatitis. J Am Acad Dermatol 2001; 44: S65-S72.
  66. Boguniewicz M, Fiedler VC, Raimer S et al. A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. J Allergy Clin Immunol 1998; 102: 637-644.
  67. Paller A, Eichenfield LF, Leung DYM et al. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 2001; 44: S47-S57.
  68. Kang S, Lucky AW, Pariser D et al. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol 2001; 44: S58-S64.
  69. Walker Metry D, Herbert AA. Topical therapies and medications in the pediatric patient. Pediatr Dermatol 2000; 47: 867-876.
  70. Hanifin JM. Use of tacrolimus ointment (TO) in 3-6 year olds with atopic dermatitis (AD): Dose-escalation study. J Invest Dermatol 1998; 110: Abstract 680.
  71. Package Insert. Protopic (Tacrolimus). Astellas Pharma Europe B.V. Elisabethhof 19 2353 EW Leiderdorp Netherlands 2009.
  72. Reitamo S, Wollenberg A, Schopf E et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. Arch Dermatol 2000; 136: 999-1006.
  73. Pournaras CC, Lubbe J, Saurat J. Staphylococcal colonization in atopic dermatitis treatment with topical tacrolimus (FK506). J Invest Dermatol 2001; 116: 480-481.
  74. Remitz A, Kyllonen H, Granlund H et al. Tacrolimus ointment reduces staphylococcal colonization of atopic dermatitis lesions. J Allergy Clin Immunol 2001; 107: 196-197.
  75. Lauerma AI, Maibach HI. Topical FK506 - clinical potential or laboratory curiosity? Dermatology 1994; 188: 173-176.
  76. Gupta AK, Adamiak A, Chow M. Tacrolimus: a review of its use for the management of dermatoses. JEADV (2002) 16, 100-114.
  77. Meingassner JG, Stutz A. Immunosuppressive macrolides of the type FK506: a novel class of topical agents for treatment of skin diseases? J Invest Dermatol 1992; 98: 851-855.
  78. Duncan JI. Differential inhibition of cutaneous T cell-mediated reactions and epidermal cell proliferation by cyclosporine A, FK- 506, and rapamycin. J Invest Dermatol 1994; 102: 84-88.
  79. Hiroi J, Sengoku T, Morita K et al. Effect of tacrolimus hydrate (FK506) ointment on spontaneous dermatitis in NC/Nga mice. Jpn J Pharmacol 1998; 76: 175-183.
  80. Doss N, Reitamo S, Dubertret L et al., Efficacy of tacrolimus 0.03% ointment as second-line treatment for children with moderate-tosevere atopic dermatitis: evidence from a randomized, double-blind non-inferiority trial vs. fluticasone 0.005% ointment. Pediatr Allergy Immunol 2009.
  81. Doss N, Kamoun M-R, Dubertret L et al., Superiority of tacrolimus 0.1% ointment compared with fluticasone 0.005% in adults with moderate to severe atopic dermatitis of the face: results from a randomized, double-blind trial. BJD 2009; 161: 427-434.
  82. Zabawski EJ, Costner M, Cohen JB et al. Tacrolimus: pharmacology and therapeutic uses in dermatology. Int J Dermatol 2000; 39: 721-727.
  83. Bos JD, Van Leent EJM. Tacrolimus (FK506): Topical inflammatory cytokine inhibitor. J Cutan Med Surg 2001; 5 (suppl. 3): 7-11.
  84. Neylor N, Elmets C, Jaracz E et al., Non-melanoma skin cancer in patients with atopic dermatitis treated with topical tacrolimus. J Dermatol Treatment 2005; 16: 149-153.
  85. Abramovits W, Fleisher AB, Jaracz E et al., Adult patients with moderate atopic dermatitis: tacrolimus ointment versus pimecrolimus cream. J Drugs Dermatol 2008; 7 (120): 1153-1158.
  86. Paller AS, Lebwohl M, Fleischer AB Jr, et al. Tacrolimus ointment is more effective than pimecrolimus cream with a similar safety profile in the treatment of atopic dermatitis: results from 3 randomized, comparative studies. J Am Acad Dermatol 2005;52:810-22.
  87. Margolis DJ, Hoffstad O, Bilker W. Lack of the association between exposure to topical calcineurine inhibitors and skin cancer in adults. Dermatology 2007; 214: 289-295.
  88. Arrelano FN, Wentworth CE, Arana A, et al., Rysk of lymphoma following exposure to calcineurine inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol 2007; 127: 808-816.
  89. Astellas Pharma GmbH. Summaries of Product Characteristics. Protopic 0.03% Ointment and Protopic 0.01% Ointment. Munich, Germany: Astellas Pharma GmbH, 2006.
  90. Vente C, Reich K, Rupprecht R, Neumann C. Erosive mucosal lichen planus: response to topical treatment with tacrolimus. Br J Dermatol 1999; 140: 338-342.
  91. Lener EV, Brieva J, Schachter M et al. Successful treatment of erosive lichen planus with topical tacrolimus. Arch Dermatol 2001; 137: 419-422.
  92. Yamamoto S, Jiang H, Kato R. Stimulation of hair growth by topical application of FK506, a potent immunosuppressive agent. J Invest Dermatol 1994; 102: 160-164.
  93. Jiang H, Yamamoto S, Kato R. Induction of anagen in telogen mouse skin by topical application of FK506, a potent immunosuppressant. J Invest Dermatol 1995; 104: 523-525.
  94. McElwee KJ, Rushton DH, Trachy R, Oliver RF. Topical FK506: a potent immunotherapy for alopecia areata? Studies using the Dundee experimental bald rat model. Br J Dermatol 1997; 137: 491-497.
  95. Maurer M, Handjiski B, Paus R. Hair growth modulation by topical immunophilin ligands; induction of anagen, inhibition of massive catagen development, and relative protection from chemotherapyinduced alopecia. Am J Pathol 1997; 150: 1433-1441.
  96. Thiers BH. Topical tacrolimus: Treatment failure in a patient with alopecia areata. Arch Dermatol 2000; 136: 124.
  97. Jiang H, Yamamoto S, Nishikawa K, Kato R. Anti-tumour-promoting action of FK506, a potent immunosuppressive agent. Carcinogenesis 1993; 14: 67-71.
  98. Yamamoto S, Jiang H, Kato R. Inhibition of anthralin-caused skin tumor promotion and interleukin-1alpha production by potent immunosuppressant FK506. Cancer Lett 1994; 83: 185-189.
  99. Fujita T, Takahashi S, Yagihashi A et al. Prolonged survival of rat skin allograft by treatment with FK506 ointment. Transplantation 1997; 64: 922-925.
  100. Yuzawa K, Taniguchi H, Seino K et al. Topical immunosuppression in skin grafting with FK506 ointment. Transplant Proc 1996; 28: 1387-1389.
  101. Casson DH, Eltumi M, Tomlin S et al. Topical tacrolimus may be effective in the treatment of oral and perineal Crohn's disease. Gut 2000; 47: 436-440.
  102. Nash RA, Etzioni R, Storb R et al. Tacrolimus (FK506) alone or in combination with methotrexate or methylprednisolone for the prevention of acute graft-versus-host disease after marrow transplantation from HLA-matched siblings: a single-center study. Blood 1995; 85: 3746-3753.
  103. Nielsen FT, Leyssac PP, Kemp E et al. Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity. Nephrol Dial Transplant 1995; 10: 334-340.
  104. Nasr IS. Topical tacrolimus in dermatology. Clin Exp Dermatol 2000; 25: 250-254.
  105. Compendium of Pharmaceuticals Specialties, 35th edn. Webcom Limited, Toronto, 2000: 1287-1292.
  106. Manez R, Jain A, Marino IR, Thomson AW. Comparative evaluation of tacrolimus (FK506) and cyclosporin A as immunosuppressive agents. Transplant Rev 1995; 9: 63-76.
  107. Nousari Hossein C, Sragovich A, Kimyai-Asadi A et al. Mycophenolate mofetil in autoimmune and inflammatory skin disorders. J Am Acad Dermatol 1999; 40: 265-268.
  108. Jonas S, Rayes N, Neumann U et al. De novo malignancies after liver transplantation using tacrolimus-based protocols or cyclosporine- based quadruple immunosuppression with an interleukin- 2 receptor antibody or antithymocyte globulin. Cancer 1997; 80: 1141-1150.
  109. Bekersky I, Ohara K, Dressler DE et al. An evaluation of the phototoxicity of tacrolimus (FK506) ointment in hairless mice. Int J Toxicol 1998; 14: 541-550.
  110. Bekersky I, Boswell G, Ohara K et al. Topical application of tacrolimus ointment did not alter the cutaneous pigmentation of Yucatan micropigs. Int J Toxicol 1999; 18: 19-21
  111. Alak AM, Cook M, Bekersky I. A highly sensitive enzyme-linked immunoabsorbent assay for the determination of tacrolimus in atopic dermatitis patients. Ther Drug Monit 1997; 19: 88-91.
  112. Soter NA, Fleischer AB, Webster GF et al. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: Part II, Safety. J Am Acad Dermatol 2001; 44: S39-S46.
  113. Etoh T. Long-term safety and efficacy of tacrolimus ointment: the Japanese experience. Immunomodulation in Focus Conference Newsletter 2000; 4-5.
  114. Rustin M. Treatment of atopic dermatitis in adults with topical tacrolimus. Immunomodulation in Focus Conference Newsletter 2000; 6.
  115. Reitamo S, Rissanen J, Remitz A et al. Tacrolimus ointment does not affect collagen synthesis; results of a single-center randomized trial. J Invest Dermatol 1998; 111: 396-398.
  116. Jaracz E, Fleischer A, Rico MJ et al. Tacrolimus ointment for the treatment of atopic dermatitis: Focus on cutaneous infections. 2001. Washington DC. Conference Proceeding.
  117. Lubbe J, Pournaras CC, Saurat J-H. Eczema herpeticum during treatment of atopic dermatitis with 0.1% tacrolimus ointment. Dermatology 2000; 201: 249-251.
  118. Navia MA. Rational design of new immunosuppressive drugs. Transplant Proc 1999; 31: 1097-1098.
  119. Wollenberg A, Reitamo S, Atzori F. et al., Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy 2008: 63: 742-750.
  120. Reitamo S, Ortonne JP, Sand C, et al. A multicentre, randomized, double-blind, controlled study of long-term treatment with 0.1% tacrolimus ointment in adults with moderate-to-severe atopic dermatitis. Br J Dermatol 2005;152:1282-9.
  121. Thaci D, Reitamo S, Ensenat MAG et al., Proactive disease management with 0.03% tacrolimus ointment for children with atopic dermatitis: results of a randomized, multicentre, comparative study BJD 2008 159, pp1348-1356.
  122. Mollison KW, Fey TA, Gauvin DM et al. A macrolactam inhibitor of T helper type 1 and T helper type 2 cytokine biosynthesis for topical treatment of inflammatory skin diseases. J Invest Dermatol 1995; 112: 729-738.
  123. Frankel D. Tacrolimus of benefit in atopic dermatitis. Lancet 1998; 352: 1604-1604.
  124. McAlister RO. Tacrolimus: a promising new therapy for eczema/ atopic dermatitis. Advocate 1999; 11: 1-9.
  125. FK506 Ointment Study Group. Phase III comparative study on FK506 ointment: intergroup comparative study on FK506 ointment and betamethasone valerate ointment in the treatment of atopic dermatitis (of the trunk and limbs). Nishi Nihon J Dermatol 1997; 59: 870-879.
  126. FK506 Ointment Study Group. Phase III comparative study on FK506 ointment and aclometasone diproprionate ointment in the treatment of atopic dermatitis. Acta Dermatol 1997; 92: 277-288.

Statistics

Views

Abstract - 439

PDF (Russian) - 273

PlumX

Article Metrics

Metrics Loading ...

Dimensions

Refbacks

  • There are currently no refbacks.

Copyright (c) 1970 Bakulev A.L., Bakulev A.L.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies